ANGPTL8 negatively regulates NF-κB activation by facilitating selective autophagic degradation of IKKγ

Excessive nuclear factor-kappa B (NF-kappa B) activation mediated by tumor necrosis factor a (TNF alpha) plays a critical role in inflammation. Here we demonstrate that angiopoietin-like 8 (ANGPTL8) functions as a negative feedback regulator in TNF alpha-triggered NF-kappa B activation intracellularly. Inflammatory stimuli induce ANGPTL8 expression, and knockdown or knockout of ANGPTL8 potentiates TNF alpha-induced NF-kappa B activation in vitro. Mechanistically, upon TNF alpha stimulation, ANGPTL8 facilitates the interaction of IKK gamma with p62 via forming a complex, thus promoting the selective autophagic degradation of IKK gamma. Furthermore, the N-terminal domain mediated self-oligomerization of ANGPTL8 is essential for IKK gamma degradation and NF-kappa B activation. In vivo, circulating ANGPTL8 level is high in patients diagnosed with infectious diseases, and the ANGPTL8/p62-IKK gamma axis is responsive to inflammatory stimuli in the liver of LPS-injected mice. Altogether, our study suggests the ANGPTL8/p62-IKK gamma axis as a negative feedback loop that regulates NF-kappa B activation, and extends the role of selective autophagy in fine-tuned inflammatory responses.